Pancreatic fibrosis, a characteristic histopathological feature of chronic pancreatitis (CP), is actually an active dynamic process that results in irreversible morphological scarring of the pancreatic parenchyma. The long-standing or recurrent inflammation of the pancreas is often associated with progressive fibrosis; thus, causes persistent abdominal pain and permanent impairment of pancreatic functions, and eventually leads to a variety of systemic complications including malabsorption and diabetes mellitus. In general, CP is commonly arisen from abnormal or over-consumption of alcohol. Besides inflammation, pancreatic fibrosis can also be idiopathic and hereditary, for example, mutations in genes PRSS1, SPINK1 and CFTR, also contribute to its development as claimed in DiMagno M J, DiMagno E P. Curr Opin Gastroenterol. 2011 September; 27(5):452-9. Several recent studies, such as Witt H. Gut. 2003 May; 52 Suppl2:ii31-41, reported that CP and fibrosis are linked with an increased risk of pancreatic cancer, especially for smokers.
A number of animal models for investigation of pancreatic fibrosis have been employed in order to allow translation to the human situation. Chronic repetitive over-stimulation with the cholecystokinin 8 (CCK8) analogue cerulein (50 μg/kg/intra-peritoneal injection) for an induction of CP is one of the most commonly used approaches, such as in Otsuki M, et al. Gastroenterol Res Pract. 2010; 2010:403295, in rodents. During the development of pancreatic fibrosis under CP conditions, the irreversible morphological scarring of pancreatic parenchyma is a prominent consequence of the active fibrotic process. In fact, the most crucial initiating step of this fibrotic process is the activation of pancreatic stellate cells (PSCs) that are generally localized at the periacinar region of the pancreas. In normal pancreas, PSCs are typically quiescent; however, in injured or fibrotic pancreas, PSCs lose their fat-droplets and transform into myofibroblast-like cells followed by the formation of stress fibers. This transformation process is so-called activation, as reported in Phillips P A, et al. Gut. 2003 May; 52(5):677-82, which can be typically identified by the expression of α-smooth muscle actin (α-SMA or Acta2). Upon tissue injury or inflammation, a variety of pro-fibrotic cytokines and hormonal factors such as transforming growth factor β (TGF-β), interleukin 1β (IL-1β), platelet-derived growth factor (PDGF) and tumor necrosis factor α·(TNF-α) trigger PSC activation, as reported in Erkan M, et al. Gut. 2012 February; 61(2):172-8. Once PSCs are activated and transformed into myofibroblast-phenotype, α-SMA and extracellular matrix (ECM) proteins including collagen I-α1 (COL I-α1) and fibronectin (FN1) are extensively expressed at the areas of active pancreatic fibrogenesis, as reported in Apte M V, et al. Gut. 1998 43: 128-133, Apte M V et al. Gut. 1999 April; 44(4):534-41 and Schneider E, et al. Am J Physiol Cell Physiol. 2001 August; 281(2):C532-43. According to recent studies such as Hu Q, et al. Nephrol Dial Transplant. 2009 October; 24(10):3033-41, TGF-β is suggested as the pivotal mediator involved in nearly all kinds of fibrotic conditions, for instance, hepatic fibrosis, pulmonary fibrosis and pancreatic fibrosis, and potently induces massive production of ECM proteins. Inflammatory disorders, regardless of their stages of acute or chronic, can be evolved with abnormal fibrotic events and accumulation of ECM proteins, and hence result in scarring of tissues that is often irreversible. In fact, the composition of fibrotic scarring is relatively common irrespective of the cause of injury or type of tissue. The progressive fibrotic process eventually leads to permanent destruction of the gland and exocrine and/or endocrine insufficiency. For that reason, the activation and proliferation of PSCs reflects the extent of fibrosis in the pancreas and in turn to be a logical target for therapeutic intervention. The immortalized rat LTC-14 cell line, established by Sparmann G et al in Sparmann G, et al. Am J Physiol Gastrointest Liver Physiol 2004 July; 287(1):G211-9, has been proved to retain the essential characteristics and morphological features of primary PSCs, and therefore this line can serve as an ideal in-vitro model for studying fibrogenesis-related mechanisms. As fibrotic pathologies are triggered or produced by the up-regulation of fibrogenic mediators, particularly α-SMA and TGF-β and the subsequent overwhelmed ECM protein synthesis, agents which can attenuate α-SMA, TGF-β and the sequential production of ECM proteins in LTC-14 cells and in cerulein-induced pancreatic tissues are of potential for treating fibrotic disorders and the associated inflammatory conditions.
It is also known, as reported in Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, Chen J, Tu M, Lu Z, Wei J, Jiang K, Miao Y. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J. Cancer. 2013 Mar. 1; 132(5):993-1003 that by producing high levels of cytokines, chemotactic factors, growth factors and excessive ECM, PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated PSCs and PDAC cells plays an important role in the development of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells, and/or by suppressing the activation of PSCs, may represent novel therapeutic approaches to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.
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